Melanoma is deadly, has a rising incidence, and is the leading cause of death from skin diseases in the United States. The survival rate for advanced cases of melanoma is less than 15%. Our ongoing research on non-coding RNAs is motivated by the pressing need to understand the molecular mechanism of melanoma genesis and to develop noncoding RNA therapeutics to fight against this form of cancer. We originally reported that miR-211 expression is high in normal human melanocytes but is significantly reduced or absent in non-pigmented melanoma cells, and its expression is also reduced in a high proportion of tissue samples from patients at different stages of melanoma progression. This miRNA is regulated by microphthalmia-associated transcription factor (MITF), and its ectopic expression in melanoma cells reduces cell growth and motility. These results suggest that miR-211 may have an important molecular function in human melanomas. Interestingly, recent results from our laboratory have shown that the depletion of miR-211 in normal human melanocytes and pigmented melanomas induces cell death, highlighting the potential role for miR-211 and its target genes in regulating melanocyte/melanoma biology. Nevertheless, the molecular mechanism by which miR-211 functions as a cell death trigger is not known. Based on our observations, we hypothesize that miR-211 and its target genes regulate senescence and apoptosis in human melanocytes and pigmented melanomas. We propose the following Specific Aims to test our hypothesis. Specific Aim 1 is focused on identification of miRNA-211 target genes in normal human melanocytes and pigmented melanoma cells to determine their contribution to senescence and/or death. Specific Aim 2 will determine the contribution of miR- 211 and its target genes in the development and progression of human melanocytic nevi and melanomas. At the end of this study, we believe that we will have sufficient evidence to justify developing antagomir based therapeutics to induce cell death in pigmented melanomas. We will also prove that miR-211 and its target genes are useful signatures in differentiating benign melanocytic nevi from their malignant counterparts.